scholarly journals Mathematical model for β1-adrenergic regulation of the mouse ventricular myocyte contraction

2020 ◽  
Vol 318 (2) ◽  
pp. H264-H282
Author(s):  
Paula D. Mullins ◽  
Vladimir E. Bondarenko
Keyword(s):  
Mathematical Model ◽  
Cardiac Myocyte ◽  
Cardiac Cycle ◽  
Adrenergic System ◽  
Signaling System ◽  
Contraction Force ◽  
Adrenergic Regulation ◽  
Experimental Protocols ◽  
Work Loop ◽  
Stimulation Of

The β1-adrenergic regulation of cardiac myocyte contraction plays an important role in regulating heart function. Activation of this system leads to an increased heart rate and stronger myocyte contraction. However, chronic stimulation of the β1-adrenergic signaling system can lead to cardiac hypertrophy and heart failure. To understand the mechanisms of action of β1-adrenoceptors, a mathematical model of cardiac myocyte contraction that includes the β1-adrenergic system was developed and studied. The model was able to simulate major experimental protocols for measurements of steady-state force-calcium relationships, cross-bridge release rate and force development rate, force-velocity relationship, and force redevelopment rate. It also reproduced quite well frequency and isoproterenol dependencies for intracellular Ca2+ concentration ([Ca2+]i) transients, total contraction force, and sarcomere shortening. The mathematical model suggested the mechanisms of increased contraction force and myocyte shortening on stimulation of β1-adrenergic receptors is due to phosphorylation of troponin I and myosin-binding protein C and increased [Ca2+]i transient resulting from activation of the β1-adrenergic signaling system. The model was used to simulate work-loop contractions and estimate the power during the cardiac cycle as well as the effects of 4-aminopyridine and tedisamil on the myocyte contraction. The developed mathematical model can be used further for simulations of contraction of ventricular myocytes from genetically modified mice and myocytes from mice with chronic cardiac diseases. NEW & NOTEWORTHY A new mathematical model of mouse ventricular myocyte contraction that includes the β1-adrenergic system was developed. The model simulated major experimental protocols for myocyte contraction and predicted the effects of 4-aminopyridine and tedisamil on the myocyte contraction. The model also allowed for simulations of work-loop contractions and estimation of the power during the cardiac cycle.

scholarly journals Distinct physiological effects of β1- and β2-adrenoceptors in mouse ventricular myocytes: insights from a compartmentalized mathematical model

2017 ◽  
Vol 312 (5) ◽  
pp. C595-C623 ◽  
Author(s):  
Kelvin Rozier ◽  
Vladimir E. Bondarenko
Keyword(s):  
Mathematical Model ◽  
Action Potential ◽  
Ventricular Myocytes ◽  
Cardiac Cells ◽  
Physiological Effects ◽  
Signaling System ◽  
Adrenergic Signaling ◽  
Signaling Systems ◽  
Physiological Conditions ◽  
Stimulation Of

The β1- and β2-adrenergic signaling systems play different roles in the functioning of cardiac cells. Experimental data show that the activation of the β1-adrenergic signaling system produces significant inotropic, lusitropic, and chronotropic effects in the heart, whereas the effects of the β2-adrenergic signaling system is less apparent. In this paper, a comprehensive compartmentalized experimentally based mathematical model of the combined β1- and β2-adrenergic signaling systems in mouse ventricular myocytes is developed to simulate the experimental findings and make testable predictions of the behavior of the cardiac cells under different physiological conditions. Simulations describe the dynamics of major signaling molecules in different subcellular compartments; kinetics and magnitudes of phosphorylation of ion channels, transporters, and Ca2+ handling proteins; modifications of action potential shape and duration; and [Ca2+]i and [Na+]i dynamics upon stimulation of β1- and β2-adrenergic receptors (β1- and β2-ARs). The model reveals physiological conditions when β2-ARs do not produce significant physiological effects and when their effects can be measured experimentally. Simulations demonstrated that stimulation of β2-ARs with isoproterenol caused a marked increase in the magnitude of the L-type Ca2+ current, [Ca2+]i transient, and phosphorylation of phospholamban only upon additional application of pertussis toxin or inhibition of phosphodiesterases of type 3 and 4. The model also made testable predictions of the changes in magnitudes of [Ca2+]i and [Na+]i fluxes, the rate of decay of [Na+]i concentration upon both combined and separate stimulation of β1- and β2-ARs, and the contribution of phosphorylation of PKA targets to the changes in the action potential and [Ca2+]i transient.

Simulation of the effects of moderate stimulation/inhibition of the β1-adrenergic signaling system and its components in mouse ventricular myocytes

2016 ◽  
Vol 310 (11) ◽  
pp. C844-C856 ◽  
Author(s):  
Mark Grinshpon ◽  
Vladimir E. Bondarenko
Keyword(s):  
Mathematical Model ◽  
Action Potential ◽  
Action Potential Duration ◽  
Ventricular Myocytes ◽  
Cardiac Cells ◽  
Protein Signaling ◽  
Signaling System ◽  
Adrenergic Signaling ◽  
Signaling Systems ◽  
Stimulation Of

The β1-adrenergic signaling system is one of the most important protein signaling systems in cardiac cells. It regulates cardiac action potential duration, intracellular Ca2+concentration ([Ca2+]i) transients, and contraction force. In this paper, a comprehensive experimentally based mathematical model of the β1-adrenergic signaling system for mouse ventricular myocytes is explored to simulate the effects of moderate stimulations of β1-adrenergic receptors (β1-ARs) on the action potential, Ca2+and Na+dynamics, as well as the effects of inhibition of protein kinase A (PKA) and phosphodiesterase of type 4 (PDE4). Simulation results show that the action potential prolongations reach saturating values at relatively small concentrations of isoproterenol (∼0.01 μM), while the [Ca2+]itransient amplitude saturates at significantly larger concentrations (∼0.1–1.0 μM). The differences in the response of Ca2+and Na+fluxes to moderate stimulation of β1-ARs are also observed. Sensitivity analysis of the mathematical model is performed and the model limitations are discussed. The investigated model reproduces most of the experimentally observed effects of moderate stimulation of β1-ARs, PKA, and PDE4 inhibition on the L-type Ca2+current, [Ca2+]itransients, and the sarcoplasmic reticulum Ca2+load and makes testable predictions for the action potential duration and [Ca2+]itransients as functions of isoproterenol concentration.

scholarly journals Role of the heart in blood pressure lowering during chronic baroreflex activation: insight from an in silico analysis

2018 ◽  
Vol 315 (5) ◽  
pp. H1368-H1382 ◽  
Author(s):  
John S. Clemmer ◽  
W. Andrew Pruett ◽  
Robert L. Hester ◽  
Radu Iliescu ◽  
Thomas E. Lohmeier
Keyword(s):  
Blood Pressure ◽  
Mathematical Model ◽  
Renal Denervation ◽  
Sympathetic Nerve Activity ◽  
Blood Pressure Lowering ◽  
Nerve Activity ◽  
Renal Sympathetic Nerve Activity ◽  
Pressure Lowering ◽  
Renal Sympathetic ◽  
Stimulation Of

Electrical stimulation of the baroreflex chronically suppresses sympathetic activity and arterial pressure and is currently being evaluated for the treatment of resistant hypertension. The antihypertensive effects of baroreflex activation are often attributed to renal sympathoinhibition. However, baroreflex activation also decreases heart rate, and robust blood pressure lowering occurs even after renal denervation. Because controlling renal sympathetic nerve activity (RSNA) and cardiac autonomic activity cannot be achieved experimentally, we used an established mathematical model of human physiology (HumMod) to provide mechanistic insights into their relative and combined contributions to the cardiovascular responses during baroreflex activation. Three-week responses to baroreflex activation closely mimicked experimental observations in dogs including decreases in blood pressure, heart rate, and plasma norepinephrine and increases in plasma atrial natriuretic peptide (ANP), providing validation of the model. Simulations showed that baroreflex-induced alterations in cardiac sympathetic and parasympathetic activity lead to a sustained depression of cardiac function and increased secretion of ANP. Increased ANP and suppression of RSNA both enhanced renal excretory function and accounted for most of the chronic blood pressure lowering during baroreflex activation. However, when suppression of RSNA was blocked, the blood pressure response to baroreflex activation was not appreciably impaired due to inordinate fluid accumulation and further increases in atrial pressure and ANP secretion. These simulations provide a mechanistic understanding of experimental and clinical observations showing that baroreflex activation effectively lowers blood pressure in subjects with previous renal denervation. NEW & NOTEWORTHY Both experimental and clinical studies have shown that the presence of renal nerves is not an obligate requirement for sustained reductions in blood pressure during chronic electrical stimulation of the carotid baroreflex. Simulations using HumMod, a mathematical model of integrative human physiology, indicated that both increased secretion of atrial natriuretic peptide and suppressed renal sympathetic nerve activity play key roles in mediating long-term reductions in blood pressure during chronic baroreflex activation.

Stimulation of Ca2+ influx in αT3–1 gonadotrophs via the cAMP/PKA signaling system

1997 ◽  
Vol 273 (5) ◽  
pp. E850-E858 ◽  
Author(s):  
Marjan Hezareh ◽  
Werner Schlegel ◽  
Stephen R. Rawlings
Keyword(s):  
Adenylate Cyclase ◽  
Calcium Concentration ◽  
Cytosolic Calcium ◽  
Camp Signaling ◽  
Signaling System ◽  
Cyclic Monophosphate ◽  
Pituitary Adenylate Cyclase ◽  
Inositol 1,4,5 Trisphosphate ◽  
Made In ◽  
Stimulation Of

To investigate the regulation of free cytosolic calcium concentration ([Ca2+]i) by the adenosine 3′,5′-cyclic monophosphate (cAMP) signaling system in clonal gonadotrophs, microfluorimetric recordings were made in single indo 1-loaded αT3–1 cells. Forskolin, 8-bromoadenosine 3′,5′-cyclic monophosphate, or a low concentration (100 pM) of the hypothalamic factor pituitary adenylate cyclase-activating polypeptide (PACAP) stimulated Ca2+ step responses or repetitive Ca2+ transients, which were blocked by the removal of extracellular Ca2+ by the dihydropyridine (DHP) (+)PN 200–110 or by preincubation with the protein kinase A (PKA) antagonist H-89 (10 μM). Thus activation of the cAMP/PKA system in αT3–1 gonadotrophs stimulates Ca2+ influx through DHP-sensitive (L-type) Ca2+ channels. In contrast, high PACAP concentrations (100 nM) stimulated biphasic Ca2+ spike-plateau responses. The Ca2+ spike was independent of extracellular Ca2+, and similar responses were observed by microperfusion of individual cells withd- myo-inositol 1,4,5-trisphosphate, suggesting the involvement of the phospholipase C (PLC) signaling pathway. The Ca2+plateau depended on Ca2+ influx, was blocked by (+)PN 200–110, but was only partially blocked by H-89 pretreatment. In conclusion, PACAP stimulates [Ca2+]iincreases in αT3–1 gonadotrophs through both the PLC and adenylate cyclase signaling pathways. Furthermore, this is the first clear demonstration that the cAMP/PKA system can mediate changes in [Ca2+]iin gonadotroph-like cells.

Effects of calcium channel antagonists on the vagally mediated cardiac chronotropic response in dogs

1990 ◽  
Vol 68 (10) ◽  
pp. 1363-1367 ◽  
Author(s):  
Don W. Wallick ◽  
Sherry L. Stuesse ◽  
Paul Martin
Keyword(s):  
Electrical Stimulation ◽  
Vagus Nerve ◽  
Calcium Channel ◽  
Total Dose ◽  
Cycle Length ◽  
Cardiac Cycle ◽  
Vagal Stimulation ◽  
Calcium Channel Antagonists ◽  
Chronotropic Response ◽  
Stimulation Of

A brief electrical stimulation of the vagus nerve may elicit a triphasic response comprising (i) an initial prolongation of the same or the next cardiac cycle, (ii) a return of the subsequent cardiac cycle to about the level prior to vagal stimulation, and (iii) a secondary prolongation of cardiac cycle length that lasts several beats. We compared the effects of two calcium channel antagonists, verapamil and nifedipine, on this triphasic response to vagal stimulation in chloralose-anesthetized, open-chest dogs. In the absence of vagal stimulation, nifedipine (doses of 10, 40, and 50 μg/kg for a total dose of 100 μg/kg, i.v.) and verapamil (two doses of 100 μg/kg each, i.v.) increased the cardiac cycle length (A–A interval) by 16% (429 ± 20 to 496 ± 21 ms) and 29% (470 ± 33 to 605 ± 54 ms), respectively. Nifedipine (100 μg/kg total) attenuated the initial vagally mediated prolongation of the A–A interval, from 474 ± 19 to 369 ± 42 ms above the basal A–A interval. Following the initial prolongation of the vagal effect, other A–A intervals were not affected. In contrast, verapamil potentiated the vagally mediated initial prolongation in cardiac cycle length at the first dose administered (100 μg/kg) from 492 ± 17 to 561 ± 14 ms, but other increases in dosages had no further effect. Thus these two calcium channel antagonists have different effects on the sinoatrial chronotropic responses caused by brief vagal stimulation.Key words: autonomic control, parasympathetic, heart, calcium.

Inhibition of rostral VLM by baroreceptor activation is relayed through caudal VLM

1990 ◽  
Vol 258 (5) ◽  
pp. R1271-R1278 ◽  
Author(s):  
S. K. Agarwal ◽  
A. J. Gelsema ◽  
F. R. Calaresu
Keyword(s):  
Kynurenic Acid ◽  
Cardiac Cycle ◽  
Pressor Response ◽  
Inhibitory Response ◽  
Firing Frequency ◽  
Ventrolateral Medulla ◽  
Cardiovascular Neurons ◽  
Baroreceptor Activation ◽  
Acid Administration ◽  
Stimulation Of

Experiments were done to test the hypothesis that inhibition of neurons in the rostral ventrolateral medulla (RVLM) elicited by stimulation of the nucleus tractus solitarii (NTS) is relayed through the caudal ventrolateral medulla (CVLM). We recorded activity from 56 spontaneously firing units in the right RVLM of urethan-anesthetized and artificially ventilated rats. Eleven of these units were classified as cardiovascular neurons, because they were silenced by baroreceptor activation (1-3 micrograms phenylephrine iv) and showed rhythmicity of their spontaneous activity in synchrony with the cardiac cycle. Single pulses (0.1 ms, 30-75 microA) delivered 1/s to depressor sites in the ipsilateral NTS inhibited the activity of all these cardiovascular neurons. Microinjection of the glutamate antagonist kynurenic acid (0.15 M, 50 nl) into the ipsilateral CVLM blocked the inhibitory response of RVLM units to the administration of phenylephrine and increased the firing frequency of cardiovascular neurons in the RVLM by 43%. Moreover, kynurenic acid administration attenuated the inhibitory response of cardiovascular neurons in the RVLM to NTS stimulation. Finally, stimulation of the NTS that elicited depressor responses under control conditions produced a pressor response after kynurenic acid administration. The remaining 45 RVLM neurons were barosensitive but lacked cardiac cycle-related rhythmicity. These results provide direct evidence for the existence of a tonic inhibitory pathway from NTS to RVLM that is relayed through the CVLM probably by a glutamatergic projection from NTS to CVLM.

scholarly journals Simulation analysis of intracellular Na+ and Cl− homeostasis during β1-adrenergic stimulation of cardiac myocyte

2008 ◽  
Vol 96 (1-3) ◽  
pp. 171-186 ◽  
Author(s):  
Masanori Kuzumoto ◽  
Ayako Takeuchi ◽  
Hiroyuki Nakai ◽  
Chiaki Oka ◽  
Akinori Noma ◽  
...  
Keyword(s):  
Cardiac Myocyte ◽  
Simulation Analysis ◽  
Adrenergic Stimulation ◽  
Stimulation Of

scholarly journals Towards a psychophysics of interoceptive processes: the measurement of heartbeat detection

2016 ◽  
Vol 371 (1708) ◽  
pp. 20160015 ◽  
Author(s):  
Jasper Brener ◽  
Christopher Ring
Keyword(s):  
Mental Health ◽  
Cardiac Cycle ◽  
Forced Choice ◽  
Human Experimentation ◽  
Direct Stimulation ◽  
Non Invasive ◽  
Objective Evidence ◽  
Interoceptive Sensitivity ◽  
Stimulation Of

It is difficult to collect objective evidence of interoception. Unlike exteroception, the effective stimuli for interoception are often unknown, and even when identifiable, they are difficult to control experimentally. Furthermore, direct stimulation of the interoceptors is seldom appropriate in human experimentation. Hence, non-invasive behavioural measures of accuracy in heartbeat detection have frequently been adopted to index interoceptive sensitivity. However, there has been little standardization and the two most popular methods for assessing heartbeat detection, heartbeat tracking and two alternative forced choice methods, appear to be biased and of questionable validity. These issues do not arise with other methods that are based on classical psychophysics and that enable subjects to indicate when during the cardiac cycle their heartbeat sensations occur. Not only are these classical methods highly reliable, but they also provide continuous unbiased measures of the temporal locations of heartbeat sensations and the precision with which these sensations are detected. This article is part of the themed issue ‘Interoception beyond homeostasis: affect, cognition and mental health’.

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